CXCR5+TIM-3-PD-1+ stem-like cytotoxic CD8+ T cells: elevated in chronic rhinosinusitis and associated with disease severity.

Background: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease with an autoimmune background. Altered expression levels of T cell immunoglobulin and mucin-domain containing-3 (TIM-3), C-X-C chemokine receptor type 5 (CXCR5), and programmed cell death protein 1 (PD-1) are implicated in the progression of inflammatory and autoimmune diseases. Moreover, CXCR5+TIM-3-PD-1+ stem-like cytotoxic T cells function as memory stem cells during chronic disease processes and retain cytotoxicity-related gene networks. Objectives: To explore the expressions of CXCR5, TIM-3, and PD-1 on T cells and their correlation with clinical parameters in CRS. Methods: Flow cytometry was used to assess the expressions and co-expressions of CXCR5, TIM-3, and PD-1 on T cells in the tissues of the paranasal sinus and peripheral blood of patients with CRS as well as healthy controls. Immunofluorescence was used to assess the co-localization of TIM-3, CXCR5, and PD-1 with T cells. The disease severity of our patients with CRS was evaluated using the Lund-Mackay score. A complete blood count was also performed for the patients with CRS. Results: Expression levels of CXCR5 and PD-1 on T cells were significantly increased in the nasal tissues of patients with CRS. Compared with those in healthy controls, patients with CRS had high percentages of CXCR5+TIM-3-PD-1+ CD8+ and CD4+ T cells in nasal tissues, while no significant difference was observed in peripheral blood levels. Patients with CRS had a higher density of nasal CXCR5+TIM-3-PD-1+ T cells than that in healthy controls. CXCR5+TIM-3-PD-1+ CD8+ T cell levels in the nasal polyps of patients with CRS were negatively correlated with the patients' Lund-Mackay scores. The levels of CXCR5+TIM-3-PD-1+ T cells in nasal tissues were also negatively associated with disease duration and positively associated with the chronic inflammatory state of CRS. Conclusions: The level of CXCR5+TIM-3-PD-1+ stem cell-like T cells, especially CXCR5+TIM-3-PD-1+ CD8+ T cells, is increased in CRS. Therefore, inducing CXCR5+TIM-3-PD-1+ T cell exhaustion may be an effective immunotherapy for CRS.

Bioengineered Hydrogels Recapitulate Fibroblast Heterogeneity in Cancer.

Recently mapped transcriptomic landscapes reveal the extent of heterogeneity in cancer-associated fibroblasts (CAFs) beyond previously established single-gene markers. Functional analyses of individual CAF subsets within the tumor microenvironment are critical to develop more accurate CAF-targeting therapeutic strategies. However, there is a lack of robust preclinical models that reflect this heterogeneity in vitro. In this study, single-cell RNA sequencing datasets acquired from head and neck squamous cell carcinoma tissues to predict microenvironmental and cellular features governing individual CAF subsets are leveraged. Some of these features are then incorporated into a tunable hyaluronan-based hydrogel system to culture patient-derived CAFs. Control over hydrogel degradability and integrin adhesiveness enabled derivation of the predominant myofibroblastic and inflammatory CAF subsets, as shown through changes in cell morphology and transcriptomic profiles. Last, using these hydrogel-cultured CAFs, microtubule dynamics are identified, but not actomyosin contractility, as a key mediator of CAF plasticity. The recapitulation of CAF heterogeneity in vitro using defined hydrogels presents unique opportunities for advancing the understanding of CAF biology and evaluation of CAF-targeting therapeutics.

Asiaticoside exerts neuroprotection through targeting NLRP3 inflammasome activation.

BACKGROUND: Parkinson's disease (PD), a neurodegenerative disorder, is characterized by motor symptoms due to the progressive loss of dopaminergic neurons in the substantia nigra (SN) and striatum (STR), alongside neuroinflammation. Asiaticoside (AS), a primary active component with anti-inflammatory and neuroprotective properties, is derived from Centella asiatica. However, the precise mechanisms through which AS influences PD associated with inflammation are not yet fully understood. PURPOSE: This study aimed to explore the protective mechanism of AS in PD. METHODS: Targets associated with AS and PD were identified from the Swiss Target Prediction, Similarity Ensemble Approach, PharmMapper, and GeneCards database. A protein-protein interaction (PPI) network was constructed to identify potential therapeutic targets. Concurrently, GO and KEGG analyses were performed to predict potential signaling pathways. To validate these mechanisms, the effects of AS on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice were investigated. Furthermore, neuroinflammation and the activation of the NLRP3 inflammasome were assessed to confirm the anti-inflammatory properties of AS. In vitro experiments in BV2 cells were then performed to investigate the mechanisms of AS in PD. Moreover, CETSA, molecular docking, and molecular dynamics simulations (MDs) were performed for further validation. RESULTS: Network pharmacology analysis identified 17 potential targets affected by AS in PD. GO and KEGG analyses suggested the biological roles of these targets, demonstrating that AS interacts with 149 pathways in PD. Notably, the NOD-like receptor signaling pathway was identified as a key pathway mediating AS's effect on PD. In vivo studies demonstrated that AS alleviated motor dysfunction and reduced the loss of dopaminergic neurons in MPTP-induced PD mice. In vitro experiments demonstrated that AS substantially decreased IL-1ß release in BV2 cells, attributing this to the modulation of the NLRP3 signaling pathway. CETSA and molecular docking studies indicated that AS forms a stable complex with NLRP3. MDs suggested that ARG578 played an important role in the formation of the complex. CONCLUSION: In this study, we first predicted that the potential target and pathway of AS's effect on PD could be NLRP3 protein and NOD-like receptor signaling pathway by network pharmacology analysis. Further, we demonstrated that AS could alleviate symptoms of PD induced by MPTP through its interaction with the NLRP3 protein for the first time by in vivo and in vitro experiments. By binding to NLRP3, AS effectively inhibits the assembly and activation of the inflammasome. These findings suggest that AS is a promising inhibitor for PD driven by NLRP3 overactivation.

The relationship between Internet use and loneliness of middle-aged and older adult people: the moderating effect of residence.

Objectives: The proportion of middle-aged and older adult people exposed to the Internet continues to grow. Internet use may have an impact on the mental health of the older adult, especially loneliness. This study analyzed the relationship between Internet use and presence of loneliness. Methods: A total of 550 person aged 45 years and above were randomly selected from a province in eastern China at the end of 2022. The outcome variable was presence of loneliness, as measured by self-report. Descriptive analysis, chi-square test and binary logistic analysis were used to analyze the data. Results: 58.3% of respondents use the Internet. Internet use could reduce the possible of reported loneliness in middle-aged and older adult people (OR = 0.652, 95%CI: 0.465, 0.940), and residence played a moderating role in the relationship between them. Middle-aged and older adults who used the Internet for 1-3 h (OR = 0.464, 95%CI: 0.275, 0.784) and 3-5 h (OR = 0.484, 95%CI: 0.247, 0.946) were less likely to felt lonely than those who used the Internet for less than 1 h per day. In addition, middle-aged and older adult people using the Internet to contact relatives and friends (OR = 0.488, 95%CI:0.292, 0.818), read the news (OR = 0.485, 95%CI:0.277, 0.848), assets management (OR = 0.297, 95%CI:0.109, 0.818) were less likely to report loneliness, while those who made online payment (OR = 3.101, 95%CI:1.413, 6.807) were more likely to report loneliness. Conclusion: There is a significant negative correlation between Internet use and presence of loneliness, but different Internet duration and content have different effects on loneliness in middle-aged and older adult people. We should pay attention to the impact of Internet use on loneliness in middle-aged and older adult people.

The Prediction of Clinical Mastitis in Dairy Cows Based on Milk Yield, Rumination Time, and Milk Electrical Conductivity Using Machine Learning Algorithms.

In commercial dairy farms, mastitis is associated with increased antimicrobial use and associated resistance, which may affect milk production. This study aimed to develop sensor-based prediction models for naturally occurring clinical bovine mastitis using nine machine learning algorithms with data from 447 mastitic and 2146 healthy cows obtained from five commercial farms in Northeast China. The variables were related to daily activity, rumination time, and daily milk yield of cows, as well as milk electrical conductivity. Both Z-standardized and non-standardized datasets pertaining to four specific stages of lactation were used to train and test prediction models. For all four subgroups, the Z-standardized dataset yielded better results than those of the non-standardized one, with the multilayer artificial neural net algorithm showing the best performance. Variables of importance had a similar rank in this algorithm, indicating the consistency of these variables as predictors for bovine mastitis in commercial farms with similar automatic systems. Moreover, the peak milk yield (PMY) of mastitic cows was significantly higher than that of healthy cows (p < 0.005), indicating that high-yielding cattle are more prone to mastitis. Our results show that machine learning algorithms are effective tools for predicting mastitis in dairy cows for immediate intervention and management in commercial farms.

Identifying potential Q-markers for quality evaluation of Zhenyuan capsule by integrating chemical analysis, network pharmacology, molecular docking, and molecular dynamics simulations.

Quality markers (Q-markers) are of great significance for quality evaluation of herbal medicines. Zhenyuan Capsule (ZYC) is a kind of Chinese patent medicine used to treat cardiovascular diseases. However, reliable and effective Q-markers for ZYC are still lacking. Herein, a UHPLC-Q/Orbitrap-MS/MS was performed to characterise the preliminary chemical profile of ZYC. A total of 86 components were characterised among which 20 constituents were unambiguously identified by reference compounds. Based on network pharmacology, seven major ginsenosides with great importance in the network were identified as Q-markers among which ginsenoside Re with the highest betweenness was screened to inhibit the development of coronary heart disease (CHD) by binding with vascular endothelial growth factor A (VEGFA). Docking and molecular dynamics simulation studies suggested that ginsenoside Re stably bound to VEGFA. Quantitative determination and chemical fingerprinting analysis were performed using HPLC-DAD. The results showed that ginsenosides screened might function as potential Q-markers for ZYC.

Targeting prostate tumor low-molecular weight tyrosine phosphatase for oxidation-sensitizing therapy.

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the ACP1 gene-is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr270. PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2-mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress.

Enhancing artistic analysis through deep learning: a graphic art element recognition model based on SSD and FPT.

For the analysis of art works, accurate identification of various elements of works through deep learning methods is helpful for artists to appreciate and learn works. In this study, we leverage deep learning methodologies to precisely identify the diverse elements within graphic art designs, aiding artists in their appreciation and learning process. Our approach involves integrating the attention mechanism into an enhanced Single Shot MultiBox Detector (SSD) model to refine the recognition of artistic design elements. Additionally, we improve the feature fusion structure of the SSD model by incorporating long-range attention mechanism information, thus enhancing target detection accuracy. Moreover, we refine the Feature Pyramid Transformer (FPT) attention mechanism model to ensure the output feature map aligns effectively with the requirements of object detection. Our empirical findings demonstrate that our refined approach outperforms the original SSD algorithm across all four evaluation metrics, exhibiting improvements of 1.52%, 1.89%, 3.09%, and 2.57%, respectively. Qualitative tests further illustrate the accuracy, robustness, and universality of our proposed method, particularly in scenarios characterized by dense artistic elements and challenging-to-distinguish categories within art compositions.

A cost-effectiveness analysis of lung cancer screening with low-dose computed tomography and a polygenic risk score.

INTRODUCTION: Several studies have proved that Polygenic Risk Score (PRS) is a potential candidate for realizing precision screening. The effectiveness of low-dose computed tomography (LDCT) screening for lung cancer has been proved to reduce lung cancer specific and overall mortality, but the cost-effectiveness of diverse screening strategies remained unclear. METHODS: The comparative cost-effectiveness analysis used a Markov state-transition model to assess the potential effect and costs of the screening strategies incorporating PRS or not. A hypothetical cohort of 300,000 heavy smokers entered the study at age 50-74 years and were followed up until death or age 79 years. The model was run with a cycle length of 1 year. All the transition probabilities were validated and the performance value of PRS was extracted from published literature. A societal perspective was adopted and cost parameters were derived from databases of local medical insurance bureau. Sensitivity analyses and scenario analyses were conducted. RESULTS: The strategy incorporating PRS was estimated to obtain an ICER of CNY 156,691.93 to CNY 221,741.84 per QALY gained compared with non-screening with the initial start age range across 50-74 years. The strategy that screened using LDCT alone from 70-74 years annually could obtain an ICER of CNY 80,880.85 per QALY gained, which was the most cost-effective strategy. The introduction of PRS as an extra eligible criteria was associated with making strategies cost-saving but also lose the capability of gaining more LYs compared with LDCT screening alone. CONCLUSION: The PRS-based conjunctive screening strategy for lung cancer screening in China was not cost-effective using the willingness-to-pay threshold of 1 time Gross Domestic Product (GDP) per capita, and the optimal screening strategy for lung cancer still remains to be LDCT screening for now. Further optimization of the screening modality can be useful to consider adoption of PRS and prospective evaluation remains a research priority.

Metagenomic binning analyses of swine manure composting reveal mechanism of nitrogen cycle amendment using kaolin.

The efficient control of nitrogen loss in composting and the enhancement of product quality have become prominent concerns in current research. The positive role of varying concentrations kaolin in reducing nitrogen loss during composting was revealed using metagenomic binning combined with reverse transcription quantitative polymerase chain reaction. The results indicated that the addition of 0.5 % kaolin significantly (P < 0.05) up-regulated the expression of nosZ and nifH on day 35, while concurrently reducing norB abundance, resulting in a reduction of NH3 and N2O emissions by 61.4 % and 17.5 %, respectively. Notably, this study represents the first investigation into the co-occurrence of nitrogen functional genes and heavy metal resistance genes within metagenomic assembly genomes during composting. Emerging evidence indicates that kaolin effectively impedes the binding of Cu/Zn to nirK and nosZ gene reductases through passivation. This study offers a novel approach to enhance compost quality and waste material utilization.

Shifting and state transformations-based adaptive tracking control for deferred full state-constrained uncertain nonlinear systems.

This paper concerns the tracking control problem of a class of uncertain nonlinear systems subject to deferred time-varying state constraints and external disturbances. The states of the system are free in the initial phase and are restricted by some time-varying constraints after a particular time. A class of novel shifting functions are defined, which make any initial states that beyond the constraint region move to the desired position (such as zero). Thereafter, a new state transformation is implemented for the shifted state, which transforms the state constraint problem into the boundedness of a new variable. Compared with the existing BLF method, this approach avoids feasibility test for virtual control variables. Adaptive backstepping control and dynamic surface control are used in system controller design and stability analysis, and the ideal tracking performance is achieved. Finally, simulation example and comparative studies are carried out to illustrate the effectiveness and outstanding characteristics of the proposed approach. Simulation results show that the proposed control scheme broadens the scope of application, shortens running time and improves control efficiency compared with the existing control strategies.

Willingness to pay for cancer prevention versus treatment in China: implications for cost-effectiveness threshold.

BACKGROUND: Empirical support for the appropriate cost-effectiveness threshold (CET) in China remains sparse. OBJECTIVE: This study aimed to estimate the willingness to pay (WTP) for cancer prevention and treatment from the perspective of healthcare policy-makers (i.e. supply side) and to investigate whether there is a difference between the estimated WTP in two scenarios. METHODS: We conducted a web-based survey from May to July 2022 among experts who offering consultation to the government. We surveyed 79 experts from a national think-tank (84.81% response rate) using contingent valuation method, a method for estimating the monetary value that individuals place on a non-market service. RESULTS: The mean WTP for two scenarios were estimated at 1.29 times of per capita Gross Domestic Product (GDP) of China and 1.90 times of per capita GDP, respectively. There was a difference between the WTP in the two scenarios and the WTP for treatment was significantly higher than prevention. CONCLUSION: The findings suggest that though there is a smaller gap between the two scenarios in China as compared to other countries, the WTP may vary under different scenarios. So there's a need to further refine the development of CET by adding parameters like prevention instead of defining one universal threshold.

Current Anti-Amyloid-ß Therapy for Alzheimer's Disease Treatment: From Clinical Research to Nanomedicine.

Recent successive approval of anti-amyloid-ß (Aß) monoclonal antibodies as disease-modifying therapies against Alzheimer's disease (AD) has raised great confidence in the development of anti-AD therapies; however, the current therapies still face the dilemma of significant adverse reactions and limited effects. In this review, we summarized the therapeutic characteristics of the approved anti-Aß immunotherapies and dialectically analyzed the gains and losses from clinical trials. The review further proposed the reasonable selection of animal models in preclinical studies from the perspective of different animal models of Aß deposition and deals in-depth with the recent advances of exploring preclinical nanomedical application in Aß targeted therapy, aiming to provide a reliable systematic summary for the development of novel anti-Aß therapies. Collectively, this review comprehensively dissects the pioneering work of Aß-targeted therapies and proposed perspective insight into AD-modified therapies.

Alterations of dynamic and static brain functional activities and integration in stroke patients.

Objective: The study aimed to investigate the comprehensive characteristics of brain functional activity and integration in patients with subcortical stroke using dynamic and static analysis methods and to examine whether alterations in brain functional activity and integration were associated with clinical symptoms of patients. Methods: Dynamic amplitude of low-frequency fluctuation (dALFF), static amplitude of low-frequency fluctuation (sALFF), dynamic degree centrality (dDC), and static degree centrality (sDC) were calculated for 19 patients with right subcortical stroke, 16 patients with left subcortical stroke, and 25 healthy controls (HC). Furthermore, correlation analysis was performed to investigate the relationships between changes in brain functional measurements of patients and clinical variables. Results: Group comparison results showed that significantly decreased dALFF in the left angular (ANG_L) and right inferior parietal gyrus (IPG_R), decreased sALFF in the left precuneus (PCUN_L), and decreased sDC in the left crus II of cerebellar hemisphere (CERCRU2_L) and IPG_R, while significantly increased sDC in the right lobule X of cerebellar hemisphere (CER10_R) were detected in patients with right subcortical stroke relative to HC. Patients with left subcortical stroke showed significantly decreased sALFF in the left precuneus (PCUN_L) but increased sDC in the right hippocampus (HIP_R) compared with HC. Additionally, the altered sDC values in the CER10_R of patients with right subcortical stroke and in the HIP_R of patients with left subcortical stroke were associated with the severity of stroke and lower extremities motor function. A correlation was also found between the altered sALFF values in the PCUN_L of patients with left subcortical stroke and lower extremities motor function. Conclusion: These findings suggest that time-varying brain activity analysis may supply complementary information for static brain activity analysis. Dynamic and static brain functional activity and integration analysis may contribute to a more comprehensive understanding of the underlying neuropathology of dysfunction in stroke patients.

ZjWRKY23 and ZjWRKY40 Promote Fruit Size Enlargement by Targeting and Downregulating Cytokinin Oxidase/Dehydrogenase 5 Expression in Chinese Jujube.

Fruit size is crucial for fruit trees, as it contributes to both quality and yield. However, the underlying mechanism of fruit size regulation remains largely unknown. Taking advantage of using a fruit double-sized bud mutant of Chinese jujube, "Jinkuiwang" and its wild type, "Jinsixiaozao", we carried out a comprehensive study on the mechanism of fruit size development in jujube. Using weighted gene coexpression network analyses, a number of candidate regulators for fruit size including those involved in hormonal signaling pathways, transcription factors, and heat shock proteins were identified. A hub gene named cytokinin oxidase/dehydrogenase 5 (ZjCKX5), responsible for cytokinin degradation, was found to play a negative role in regulating fruit size development, and overexpressing ZjCKX5 in tomato and Arabidopsis resulted in much smaller fruits and dwarf plants. Furthermore, another two hub genes, ZjWRKY23 and ZjWRKY40 transcription factors, were found to participate in fruit size regulation by targeting and downregulating the ZjCKX5 expression. Overexpressing ZjWRKY23 or ZjWRKY40 in tomato led to much larger fruits and promoted plant architecture. Based on these results, a molecular framework for jujube fruit size regulation, namely, ZjWRKY-ZjCKX5 module, was proposed. This study provides a new insight into the molecular networks underlying fruit size regulation.

Docetaxel liposomes for lung targeted delivery: development and evaluation.

Docetaxel (DTX) is an artificial semi-synthetic second-generation taxane anti-tumor drug, which is suitable for the treatment of various cancers such as lung cancer. The route of administration of DTX formulations has been extended to oral, intravenous, and rectal, with few studies on pulmonary administration being reported. Here, we had developed DTX liposomes (DTX-lips) for pulmonary inhalation administration. The particle size of the preparation was 125 nm, the encapsulation efficiency was 94.4 ± 0.14%, and the drug loading capacity was 1.26 ± 0.01%. It had good stability. The fine particle fraction with aerodynamic diameter less than 6.4 µm accounts for 64.63 ± 0.12%, showed excellent aerosolization performance. DTX-lips were slow to release in simulated lung fluid. The fluorescence distribution experimented in mice and tissues showed that the fluorescence of the inhaled liposome group was mainly distributed in the lung, and the retention time was significantly prolonged as compared with those of the other two groups. No significant fluorescence was observed in other tissues, which was conducive to the full effect of the drug in the lung tissue. DTX-lips had no damage to respiratory system and whole body. These results indicated that the inhaled DTX-lips had good lung targeting, reduced accumulation in other organs, and improved the safety and effectiveness of the drug.

Maize Genotypes Sensitive and Tolerant to Low Phosphorus Levels Exhibit Different Transcriptome Profiles under Talaromyces purpurogenus Symbiosis and Low-Phosphorous Stress.

Talaromyces purpurogenus, an endophytic fungus, exhibits beneficial effects on plants during plant-fungus interactions. However, the molecular mechanisms underlying plants' responses to T. purpurogenus under low-phosphorous (P) stress are not fully understood. In this study, we investigated the transcriptomic changes in maize with low-P-sensitive (31778) and -tolerant (CCM454) genotypes under low-P stress and its symbiotic interaction with T. purpurogenus. Its colonization enhanced plant growth and facilitated P uptake, particularly in 31778. Transcriptome sequencing revealed that 135 DEGs from CCM454 and 389 from 31778 were identified, and that only 6 DEGs were common. This suggested that CCM454 and 31778 exhibited distinct molecular responses to T. purpurogenus inoculation. GO and KEGG analysis revealed that DEGs in 31778 were associated with nicotianamine biosynthesis, organic acid metabolic process, inorganic anion transport, biosynthesis of various secondary metabolites and nitrogen metabolism. In CCM454, DEGs were associated with anthocyanin biosynthesis, diterpenoid biosynthesis and metabolic process. After T. purpurogenus inoculation, the genes associated with phosphate transporter, phosphatase, peroxidase and high-affinity nitrate transporter were upregulated in 31778, whereas AP2-EREBP-transcription factors were detected at significantly higher levels in CCM454. This study provided insights on the molecular mechanisms underlying plant-endophytic fungus symbiosis and low-P stress in maize with low-P-sensitive and -tolerant genotypes.

Value for Money of CAR-T Cell Therapy for Patients with Diffuse Large B-cell Lymphoma in China: Evidence from a Cost-Effectiveness Analysis.

OBJECTIVE: This research assesses the cost effectiveness of Axicabtagene ciloleucel (Axi-cel), Tisagenlecleucel (Tis-cel), Relmacabtagene autoleucel (Rel-cel) and Lisocabtagene maraleucel (Lis-cel) against standard of care (SOC) for patients with diffuse large B-cell lymphoma (DLBCL) in the first-line setting (1L), second-line setting (2L) and third-line or later setting (3L+). METHODS: Markov modelling based on a flexible survival model was adopted to evaluate four chimeric antigen receptor T-cell (CAR-T) therapies compared with SOC for patients with diffuse large B-cell lymphoma (DLBCL). The clinical inputs and utility values of the model were derived from the most recent clinical trials and the health care costs from a Chinese provincial clinical center. Costs and quality-adjusted life years (QALYs) were used to derive incremental cost-effectiveness ratios (ICERs) from the Chinese health care system perspective. RESULTS: The ICER of Axi-cel (1L) versus SOC was approximately Chinese Yuan (CNY) 2,125,311 per QALY. The ICER for Axi-cel (2L), Tis-cel (2L) and Liso-cel (2L)) versus SOC in transplant-eligible patients were approximately CNY363,977, CNY32,066,781 and CNY347,746 per quality-adjusted life year (QALY), respectively. The ICER for Liso-cel (2L) versus SOC in transplant-ineligible patients was approximately CNY1,233,972 per QALY. The ICERs for Axi-cel (3L+), Tis-cel (3L+), Rel-cel (3L+) and Liso-cel (3L+) versus SOC were approximately CNY346,009, CNY654,344, CNY280,964 and CNY436,858 per QALY, respectively. In the scenario analysis using mixture cure models, the long-term survival benefit for CAR-T and SOC groups was found higher, and only Rel-cel (3L+) was found to be cost effective. CONCLUSION: Our results demonstrated that CAR-T treatments are not cost effective in any-line settings for DLBCL patients at the WHO-recommended willingness-to-pay threshold (CNY257,241 per QALY) in the base-case analysis. Price reduction of CAR-T therapies is the main approach for lowering ICERs and ensuring that the drug costs are proportional to patient health benefits.

GaN/Gr (2D)/Si (3D) Combined High-Performance Hot Electron Transistors.

To overcome the problem of minority carrier storage time in bipolar transistors, a hot electron transistor (HET) has been proposed. This device has the advantage of high working speed and some complex logic functions can be completed by using one component. Here, we demonstrate a mixed-dimensional HET composed of GaN/AlN microwires, graphene (Gr), and Si. The electrons between GaN/AlN are injected into graphene by an F-N tunneling mechanism to achieve high speed hot electrons, then cross graphene by ballistic transport, and are collected in a nearly lossless manner through a low-barrier Si. Therefore, the device shows a record DC gain of 16.2, a collection efficiency close to the limit of 99.9% based on the graphene hot electron transistor (GHET), an emitter current density of about 68.7 A/cm2, and a high on/off current ratio reaching ∼107. Meanwhile, the current saturation range is wide, beyond those of most GHETs. It has potential applications as a power amplifier.